Racemic threo-methylphenidate hydrochloride is an amphetamine-like prescription stimulant which is marketed for the treatment of Attention Deficit Hyperactivity Disorder in children and adults. Studies of racemic threo-methylphenidate have indicated that the d-threo-enantiomer is much more active than the corresponding l-threo-enantiomer. Furthermore, the l-threo-methylphenidate enantiomer has been postulated to impart side effects and euphoric effects.
Several methods have been disclosed in the literature for preparing the d-threo enantiomer of methylphenidate hydrochloride.
Methods for resolving threo methylphenidate into its enantiomers involve using 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate as a resolving agent have been proposed. Methods employing expensive 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate as a resolving agent are disclosed in Patrick et al (The Journal of Pharmacology and Experimental Therapeutics, 241:152-158 (1987)) and U.S. Pat. No. 6,162,919.
Several methods for resolving threo-methylphenidate free base have also been disclosed. Resolution of threo-methylphenidate is taught in U.S. Pat. No. 6,121,453 and 6,242,464, for example. The preparation and isolation of the threo-methylphenidate free base prior to resolution makes large scale preparation cumbersome.
Resolutions of threo-methylphenidate hydrochloride using aroyltartaric acids are described in U.S. Pat. No. 6,100,401 and Tetrahedron (Asymmetry) 10: 311-3116 (1999). These resolutions take place in aqueous methanol with threo-methylphenidate hydrochloride, di-p-isopropylbenzoyl- and benzoyl-D-tartaric acids and N-methylmorpholine taken in equimolar amounts.
Methods involving resolution of amide derivatives, followed by hydrolysis and esterification are also known, as described in U.S. Pat. No. 2,957,880 and Published U.S. application No. 2006/135777.
Two step resolutions are known in the art as well. Such methods involve two separate resolution steps utilizing two different resolution agents, as disclosed in Published U.S. application No. 2005/171155. Such two step resolutions are problematic in that they slow productivity and thus increase cost.
Accordingly, there remains a need in the art for a more practical, robust and economic process for preparing the d-threo isomer of methylphenidate hydrochloride.